PROJECT SUMMARY Asthma is a chronic inflammatory lung disease for which there is no cure. Allergen specific CD4 T helper (Th) cells mediate processes which characterize the majority of asthma pathogenesis. After encountering antigen, memory cells can circulate or reside in non-lymphoid tissues providing antigen specific secondary responses. This proposal focuses on the tissue-resident memory (Trm) T cells that remain tissue-bound. In our preliminary data we identified lung Trm cells in a model of allergic airway disease that produce a polarized cytokine profile including the production of IL-9 similar to Th9 cells. We have further characterized in a chronic exposure to allergen and in a memory recall response that these Th9-like Trm cells are maintained in the tissue and provide a robust secondary response. In the single Aim, we will use parallel approaches to examine the development and function of IL-9-secreting Trm cells. In the first sub-aim, we will use Th9 transcription factor-deficient mice to examine differences in Trm cell development. In the second sub-aim, we will examine IL-9 effector function in recall responses. Lastly in the third sub-aim, we will determine if IL-9-secreting Trm cells are sufficient to mediate allergic airway inflammation. Together this Aim will explore the functionality of a pro-allergic subset sharing a phenotype similar to what has been associated with allergic disease is patients. These studies will define novel contributions of CD4 Trm T cells to allergic inflammation in the lung and potentially identify new pathways as targets for therapeutic intervention in persistent asthma.